Relapse to cocaine use remains a significant challenge in the treatment of cocaine addiction, yet our understanding of those neural systems that enable individuals to inhibit cocaine seeking and relapse remains poor. The long-term goal of our laboratory is to identify the neural circuits and the changes in those circuits that underlie the inhibition of cocaine-seeking behavior, using rat models of cocaine seeking. The current proposal builds upon the findings we have obtained in recent years as well as new approaches we have developed in our laboratory. In our studies, rats undergo cocaine self-administration, extinction training and reinstatement testing of their cocaine seeking. We have found that the infralimbic cortex is a central component of the systems involved in the extinction and inhibition of cocaine-seeking behavior. Activity in the infralimbic cortex is necessary for the normal encoding of the extinction learning as well as extinction expression. For example, infralimbic activation inhibits cocaine seeking following extinction training. However, the larger circuit in which the infralimbic cortex performs these functions remains unclear. In particular, as evidence suggests functional heterogeneity within the infralimbic cortex in terms of its role in cocaine seeking, understanding the larger circuitry may provide insight into these issues. The proposed work will focus on the specific pathways projecting into and out of the infralimbic that account for its role in extinction and inhibition of cocaine seeking. The work will include approaches that have not, to our knowledge, been used in studies of cocaine seeking and, therefore, will enable notable progress in our knowledge of these systems. In particular, our studies will use multi-site recordings of neural activity during cocaine seeking to understand how a network of brain regions coordinates behavior. Moreover, the proposed studies will use optogenetic approaches to examine how different pathways mediate different aspects of the extinction and inhibition of cocaine seeking. The findings from this work will reveal those specific pathways and network activity related to the IL with regard to the extinction/inhibition of cocaine seeking. Furthermore, the proposed work will both 1) examine changes in IL-based circuits as a consequence of cocaine self-administration and extinction and 2) manipulate these circuits to determine how they functionally control the inhibition of cocaine seeking. The findings from the studies will furnish critical new basic knowledge of the neural systems underlying the suppression of cocaine seeking that will potentially lead to the development of more effective treatments that strengthen such systems in cocaine-addicted individuals.